Neurogenetics

, Volume 5, Issue 4, pp 229–238 | Cite as

Mutation in the gene encoding lysosomal acid phosphatase (Acp2) causes cerebellum and skin malformation in mouse

  • Ashraf U. Mannan
  • Elena Roussa
  • Cornelia Kraus
  • Micheal Rickmann
  • Joerg Maenner
  • Karim Nayernia
  • Kerstin Krieglstein
  • André Reis
  • Wolfgang Engel
Original Article

Abstract.

We report a novel spontaneous mutation named nax in mice, which exhibit delayed hair appearance and ataxia in a homozygote state. Histological analyses of nax brain revealed an overall impairment of the cerebellar cortex. The classical cortical cytoarchitecture was disrupted, the inner granule cell layer was not obvious, the Purkinje cells were not aligned as a Purkinje cell layer, and Bergmann glias did not span the molecular layer. Furthermore, histological analyses of skin showed that the hair follicles were also abnormal. We mapped the nax locus between marker D2Mit158 and D2Mit100 within a region of 800 kb in the middle of chromosome 2 and identified a missense mutation (Gly244Glu) in Acp2, a lysosomal monoesterase. The Glu244 mutation does not affect the stability of the Acp2 transcript, however it renders the enzyme inactive. Ultrastructural analysis of nax cerebellum showed lysosomal storage bodies in nucleated cells, suggesting progressive degeneration as the underlying mechanism. Identification of Acp2 as the gene mutated in nax mice provides a valuable model system for studying the role of Acp2 in cerebellum and skin homeostasis.

Keywords

Mutant mouse strain Genetic linkage Cerebellum Hair follicle Lysosomal storage diseases 

Supplementary material

Table S1 Summary of genes reported in nax locus

supp.pdf (12 kb)
(PDF 13 KB)

References

  1. 1.
    Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–145CrossRefPubMedGoogle Scholar
  2. 2.
    Gieselmann V (1995) Lysosomal storage diseases. Biochim Biophys Acta 1270:103–136PubMedGoogle Scholar
  3. 3.
    Drexler HG, Gignac SM (1994) Characterization and expression of tartrate-resistant acid phosphatase (TRAP) in hematopoietic cells. Leukemia 8:359–368PubMedGoogle Scholar
  4. 4.
    Gieselmann V, Hasilik A, Figura K von (1984) Tartrate-inhibitable acid phosphatase. Purification from placenta, characterization and subcellular distribution in fibroblasts. Hoppe Seyler Z Physiol Chem 365:651–660PubMedGoogle Scholar
  5. 5.
    Clark SA, Ambrose WW, Anderson TR, Terrell RS, Toverud SU (1989) Ultrastructural localization of tartrate-resistant, purple acid phosphatase in rat osteoclasts by histochemistry and immunocytochemistry. J Bone Miner Res 4:399–405PubMedGoogle Scholar
  6. 6.
    De Duve C (1959) Subcellular particles. In: Hayashi T (ed) Ronald Press, pp 128–159Google Scholar
  7. 7.
    Geier C, Kreysing J, Boettcher H, Pohlmann R, Figura K von (1992) Localization of lysosomal acid phosphatase mRNA in mouse tissues. J Histochem Cytochem 40:1275–1282PubMedGoogle Scholar
  8. 8.
    Hille A, Klumperman J, Geuze HJ, Peters C, Brodsky, FM, Figura K von (1992) Lysosomal acid phosphatase is internalized via clathrin-coated pits. Eur J Cell Biol 59:106–115PubMedGoogle Scholar
  9. 9.
    Braun M, Waheed A, Figura K von (1989) Lysosomal acid phosphatase is transported to lysosomes via the cell surface. EMBO J 8:3633–3640PubMedGoogle Scholar
  10. 10.
    Gottschalk S, Waheed A, Schmidt B, Laidler P, Figura K von, (1989) Sequential processing of lysosomal acid phosphatase by a cytoplasmic thiol proteinase and a lysosomal aspartyl proteinase. EMBO J 8:3215–3219PubMedGoogle Scholar
  11. 11.
    Saftig P, Hartmann D, Lüllmann-Rauch R, Wolff J, Evers M, Köster A, Hetman M, Figura K von, Peters C (1997) Mice deficient in lysosomal acid phosphatase develop lysosomal storage in the kidney and central nervous system. J Biol Chem 272:18628–18634CrossRefPubMedGoogle Scholar
  12. 12.
    Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkGoogle Scholar
  13. 13.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  14. 14.
    Waheed A, Van Etten RL, Gieselmann V, Figura K von (1985) Immunological characterization of human acid phosphatase gene products. Biochem Genet 23:309–319PubMedGoogle Scholar
  15. 15.
    Rickmann M, Wolff JR (1995) S100 protein expression in subpopulations of neurons of rat brain. Neuroscience 67:977–991CrossRefPubMedGoogle Scholar
  16. 16.
    Mannan AU, Nayernia K, Mueller C, Burfeind P, Adham IM, Engel W (2003) Male mice lacking the Theg (testicular haploid expressed gene) protein undergo normal spermatogenesis and are fertile. Biol Reprod 69:788–796PubMedGoogle Scholar
  17. 17.
    Hatten ME, Heintz N (1995) Mechanisms of neural patterning and specification in the developing cerebellum. Annu Rev Neurosci 18:385–408PubMedGoogle Scholar
  18. 18.
    Hatten ME (1990) Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain. Trends Neurosci 13:179–184CrossRefPubMedGoogle Scholar
  19. 19.
    Paus R, Muller-Rover S, Van Der Veen C, Maurer M, Eichmuller S, Ling G, Hofmann U, Foitzik K, Mecklenburg L, Handjiski B (1999) A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J Invest Dermatol 113:523–532CrossRefPubMedGoogle Scholar
  20. 20.
    Jakob CG, Lewinski K, Kuciel R, Ostrowski W, Lebioda L (2000) Crystal structure of human prostatic acid phosphatase. Prostate 42:211–218CrossRefPubMedGoogle Scholar
  21. 21.
    Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna I, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93:11173–11178CrossRefPubMedGoogle Scholar
  22. 22.
    Hess EJ (1996) Identification of the weaver mouse mutation: the end of the beginning. Neuron 16:1073–1076CrossRefPubMedGoogle Scholar
  23. 23.
    Miyata T, Nakajima K, Mikoshiba K, Ogawa M (1997) Regulation of Purkinje cell alignment by reelin as revealed with CR-50 antibody. J Neurosci 17:3599–3609PubMedGoogle Scholar
  24. 24.
    Goldowitz D, Cushing RC, Laywell E, D’Arcangelo G, Sheldon M, Sweet HO, Davisson M, Steindler D, Curran T, (1997) Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J Neurosci 17:8767–8777PubMedGoogle Scholar
  25. 25.
    Nakamura M, Sundberg JP, Paus R (2001) Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: annotated tables. Exp Dermatol 10:369–390CrossRefPubMedGoogle Scholar
  26. 26.
    Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, Schmidt P, Schmahl W, Scherer J, Anton-Lamprecht I, Figura K von, Paus R, Peters C (2000) Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J 14:2075–2086CrossRefPubMedGoogle Scholar
  27. 27.
    Suter A, Everts V, Boyde A, Jones SJ, Lullmann-Rauch R, Hartmann D, Hayman AR, Cox TM, Evans MJ, Meister T, Figura K von, Saftig P (2001) Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice. Development 128:4899–4910PubMedGoogle Scholar
  28. 28.
    Fusek M, Vetvicka V (1994) Mitogenic function of human procathepsin D: the role of the propeptide. Biochem J 303:775–780PubMedGoogle Scholar
  29. 29.
    Vetvicka V, Vetvickova J, Fusek M (1998) Effect of procathepsin D and its activation peptide on prostate cancer cells. Cancer Lett 129:55–59CrossRefPubMedGoogle Scholar
  30. 30.
    Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83:481-489CrossRefPubMedGoogle Scholar
  31. 31.
    Walkley SU (1998) Cellular pathology of lysosomal storage disorders. Brain Pathol 8:175–193PubMedGoogle Scholar
  32. 32.
    Munoz R MV, Santos AC, Graziadio C, Pina-Neto JM (1997) Cerebello-trigeminal-dermal dysplasia (Gomez-Lopez-Hernandez syndrome): description of three new cases and review. Am J Med Genet 72:34–39CrossRefPubMedGoogle Scholar
  33. 33.
    Keeler LC, Marsh SE, Leeflang EP, Woods CG, Sztriha L, Al-Gazali L, Gururaj A, Gleeson JG (2003) Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 73:656–662CrossRefPubMedGoogle Scholar
  34. 34.
    Valente EM, Salpietro DC, Brancati F, Bertini E, Galluccio T, Tortorella G, Briuglia S, Dallapiccola B (2003) Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet 73:663–670CrossRefPubMedGoogle Scholar
  35. 35.
    Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM (1994) Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 8:280–284CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ashraf U. Mannan
    • 1
  • Elena Roussa
    • 2
  • Cornelia Kraus
    • 3
  • Micheal Rickmann
    • 2
  • Joerg Maenner
    • 2
  • Karim Nayernia
    • 1
  • Kerstin Krieglstein
    • 2
  • André Reis
    • 3
  • Wolfgang Engel
    • 1
  1. 1.Institute of Human GeneticsUniversity of GoettingenGoettingenGermany
  2. 2.Center of AnatomyUniversity of GoettingenGermany
  3. 3.Institute of Human GeneticsUniversity of Erlangen-NurembergErlangenGermany

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